This editorial includes summaries of two studies: the first is an experimental study in men looking at the effects of testosterone deficiency on body composition, strength and sexual function;1 the second is a post-observational surveillance study (IPASS) investigating the tolerability of long-acting testosterone undecanoate (TU) in men with testosterone deficiency syndrome (hypogonadism) in a clinical practice setting.2

The classification of low testosterone levels – at least 2 standard deviations below the mean value for healthy young adults – does not take into account the physiological consequences of various testosterone levels. In particular the implications of the concomitant decline in serum levels of estradiol, a metabolite of testosterone, are generally not considered. This summary describes the results from an experimental study in two cohorts of healthy men, both of whom received goserelin acetate to suppress endogenous testosterone and estradiol (Cohort 1; n=198; Cohort 2; n=202).1 Participants were randomly assigned to receive placebo, 1.25 g, 2.5 g, 5 g or 10 g of testosterone gel daily for 16 weeks. In order to differentiate between the effects of testosterone and estradiol, participants in Cohort 2 also received anastrozole 1 mg daily, an aromatase inhibitor, to block the conversion of testosterone to estradiol. The primary outcome variables were changes in percentage of body fat and total-body lean mass. Changes in subcutaneous- and intraabdominal-fat areas, thigh-muscle area and leg-press strength, and sexual function were also assessed.

The prospective, observational IPASS was conducted in 23 countries in Europe, Asia, Latin America, and Australia and investigated the safety and efficacy of intramuscular injections of TU in men with hypogonadism in a “real-life setting”.2
A total of 1493 men (age 49.2 ± 13.9 years; 72.5% Caucasian) with hypogonadism were enrolled into the study to receive up to five injections of TU over an observation period of
9–12 months. The first and second injections were given at intervals of 6–10 weeks, and subsequent injections at intervals of 12 ± 2 weeks. Patients subjectively assessed the intensity of hypogonadism-related symptoms at each study visit, and at the end of the treatment period gave a rating of overall tolerability. Laboratory measurements, including prostate-specific antigen (PSA), hemoglobin, hematocrit, and lipid profiles, as well as digital rectal examination were also assessed at each study visit. At baseline and the time of the fifth injection a total of 1438 and 1140 men were evaluable, respectively. At baseline, body weight was 86.8 ± 17.6 kg, waist circumference 99.5 ± 15.25 cm and serum testosterone 9.6 ± 7.5 nmol/L.
The summary of this study reports the results for the safety, anthropometric and sexual function measurements.

The randomized controlled study showed that there was considerable variation in the dose of testosterone required to prevent adverse changes in body composition1

In Cohort 1 a significant increase in the percentage of body fat was observed with testosterone 1.25 g and 2.5 g and placebo, compared with testosterone 5 g.1 There was a significant decrease in the percentage of body fat with testosterone 10 mg compared with other doses.1 In Cohort 2 the percentage of body fat increased by a similar magnitude with all doses of testosterone1

The cohort-testosterone dose interaction was significant for the percentage of body fat, subcutaneous fat, and intraabdominal fat (Table 1)

An independent effect of estradiol on these measures was further confirmed by comparison of Cohort 2 (inhibition of estradiol synthesis) with Cohort 1 (intact estradiol synthesis) where testosterone was associated with significant increases in the percentage of body fat, subcutaneous fat, and intraabdominal fat (Table 1)

Both testosterone and estradiol are needed for regulation of sexual function1

In the IPASS study, TU was well tolerated and adverse drug reactions (ADRs) related to TU were rare (5.8%) in men with hypogonadism2

There was a significant decrease in waist circumference (no previous testosterone p<0.0001; pre-treated p=0.003) and a slight decrease in body weight (p=0.08) at the time of the fifth injection2

What is known

Decreases in lean mass and strength, an increase in fat mass, and impaired sexual function are generally considered to be the result of low testosterone levels. Furthermore, these changes can be reversed by testosterone replacement.3,4-8 However, it is difficult to distinguish between the effects of testosterone and estrogen in the absence of aromatase inhibition.

The aim of testosterone treatment in men with hypogonadism is to achieve normal endogenous levels. TU is a long-acting, intramuscular formulation of testosterone that produces plasma levels which are nearly always in the normal range in men.9,10 Whilst the safety profile of TU has been established in previous studies,9-11 the IPASS study aimed to confirm the safety profile of TU in a ‘real world’ setting, and in the largest worldwide sample of men with hypogonadism.

What these studies add

On the basis that there was considerable variation in the dose of testosterone required to prevent adverse changes, testosterone treatment should be individualized. These findings also provide a physiological basis for interpretation of testosterone levels. It may be more appropriate to consider the decline in gonadal steroids as a continuum rather than a rigid threshold, below which adverse changes occur. Testosterone deficiency led to a decrease in total-body lean mass, thigh-muscle area and leg-press strength, and estrogen deficiency played a role in the increases in body fat.1 An increase in intrabdominal fat may suggest an increase in cardiovascular disease if there is long-term estrogen deficiency. In men with hypogonadism measurement of estradiol levels may be helpful in evaluating the risk of fat accumulation as well as bone loss and sexual dysfunction.

The IPASS study confirmed the established safety profile of TU in the largest worldwide sample of men with testosterone deficiency.2 Furthermore, this is the first trial to be conducted in a large Asian and South American population. Whilst the anthropometric measurements are different to those discussed in the experimental study of Finkelstein and colleagues,1 the IPASS study confirms that favourable effects of testosterone replacement in the ‘real-world’ setting. In particular, a decrease in waist circumference is associated with a reduced risk of cardiovascular disease. The beneficial effects of TU on sexual function were also confirmed.